Sleep is a vital factor in many affective disorders, such as e.g. depression and the treatment of depression. In fact, sleep disruption is a major symptom of depression, and often it is the sleep disruption that causes a patient suffering from depression to seek help. In light of this, it is important that any medical intervention offered to the depressed patient ameliorates the sleep disturbances and, certainly, that it does not itself add to the sleep problems. The same, of course holds true for the treatment of other affective disorders.
Standard medical treatment of affective disorders includes compounds having the effect of increasing the level of the monoamine neurotransmitters serotonin and/or noradrenaline in the brain. Despite the fact that these medicaments are used for the treatment of a wide variety of affective disorders, they are normally referred to as “antidepressants”. The most wide spread treatment modalities include selective serotonin reuptake inhibitors (SSRI) which increase the level of serotonin, well-known and marketed examples of which include escitalopram, fluoxetine and setraline. Selective noradrenalin reuptake inhibitors (NRI) increase the level of noradrenalin, one example of which is reboxetine. Other compounds inhibit both the serotonin and the noradrenalin reuptake and are referred to as SNRI. Prominent examples of this group of medicaments include venlafaxine and duloxetine. Finally, the group of medicaments referred to as tri-cyclic amines (TCA) is widely used in the treatment of depression, and members of this group of compounds tend to have a broader pharmacological profile with an effect on other brain receptors, such as acetylcholine, adrenergic and histamine receptors, on top of an inhibiting effect on the serotonin and noradrenalin transporters.
Unfortunately, sleep disturbances seem to be a general adverse affect of most antidepressants. In particular, SSRI, NRI and SNRI are reported to give rise to problems with sleep initiation and maintenance and problems with insomnia are often reported, too [Int. Clin. Psychpharm., 21 (suppl 1), S25-S29, 2006]. Others report that such compounds give rise to suppressed REM sleep, increased sleep latency, less efficient sleep, increase in nocturnal awakenings, and fragmentation of sleep [Hum. Psychopharm. Clin. Exp., 20, 533-559, 2005].
It is generally speculated that the adverse sleep effects are caused by stimulation of the 5-HT2A receptor. R. L. Fish reports in Bioorg. Med. Chem. Lett., 15, 3665-3669, 2005 that certain 4-fluorosulfonylpiperidines, which are highly selective 5-HT2A antagonists are effective in increasing the slow wave sleep duration and decreasing the number of awakenings in rats. These pre-clinical observations are confirmed by clinical findings. Ritanserin, a 5-HT2A antagonist, has been shown to increase the total sleep time, the slow wave sleep duration, the REM sleep duration, and improve the subjective sleep quality in humans [Clin. Neurophys. 113, 429-434, 2002]. Nefazodone, a potent inhibitor of 5-HT2A and a weak inhibitor of the serotonin and the noradrenalin reuptake, has in clinical trials been shown to increase sleep continuity and total REM sleep time, and to reduce the number of awakenings [Biol. Psychiatry, 44, 3-14, 1998]. Similarly, trazodone, which is a 5-HT2A antagonist and a moderate inhibitor of the serotonin reuptake, has been shown to improve the clinical scores HAS (sleep disorders) and HRSD (premature morning awakening, lack of sound sleep and initiating sleep) [Psychiatr. Clin. Neurosci., 53, 193-194, 1999].
The above findings and observations suggest that the identification of compounds having an inhibitory effect of the serotonin and/or noradrenalin reuptake in combination with a 5-HT2A antagonistic activity would provide compounds suitable for the treatment of affective disorders, such as e.g. depression, without or with reduced adverse sleep effects, or wherein the sleep quality of the depressed patient is even improved.
The use of compounds having noradrenalin reuptake inhibitory effects brings about an increase in the level of noradrenalin, which is the cause of the therapeutic effect in the treatment of affective disorders. Noradrenalin, however, also has peripheral effects, e.g. increased heart rate, blood vessel constriction and a consequent increase in blood pressure. These peripheral effects transpire in the adverse effects reported for noradrenalin reuptake inhibitors. Venlafaxine and duloxetine, both of which are noradrenalin and serotonin reuptake inhibitors, are reported to give rise to an increase in blood pressure [Curr. Ther. Res., 66, 522-540, 2005; J. Clin. Psychiatry, 59, 502-508, 1998]. An increase in blood pressure is problematic in general, and in patients already suffering from increased blood pressure (hypertensives), e.g. elderly people, in particular.
Antagonists of the alpha1 adrenergic receptor (α1 receptor) are known to give rise to peripheral vasodilation and the consequent reduction in blood pressure due to reduced flow resistance [Clin Ther., 26, 1701-1713, 2004].
The above findings and observations suggest that the identification of compounds having an inhibitory effect on the serotonin and/or noradrenalin reuptake in combination with a α1 receptor antagonistic activity would provide compounds suitable for the treatment of affective disorders, such as e.g. depression, without or with reduced adverse cardiovascular effects, such as e.g. increased blood pressure.
The international patent application published as WO 2005/061455 discloses that certain 2-(1H-indolylsulfanyl)benzyl amine derivatives, and in particular [2-(6-fluoro-1H-indol-3-ylsulfanyl)benzyl]methyl amine are serotonin reuptake inhibitors and probably also noradrenalin reuptake inhibitors. The compounds are said to be useful for the treatment of affective disorders, such as e.g. depression.